Assessment of Novel Genome-Wide Significant Gene Loci and Lesion Growth in Geographic Atrophy Secondary to Age-Related Macular Degeneration

Felix Grassmann, Sebastian Harsch, Caroline Brandl, Christina Kiel, Peter Nürnberg, Mohammad R. Toliat, Monika Fleckenstein, Maximilian Pfau, Steffen Schmitz-Valckenberg, Frank G. Holz, Emily Y. Chew, Anand Swaroop, Rinki Ratnapriya, Michael Klein, Zufar Mulyukov, Parisa Zamiri, Bernhard H.F. Weber

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Importance: Age-related macular degeneration (AMD) is a common threat to vision loss in individuals older than 50 years. While neovascular complications in AMD are treatable, there is currently no therapy for geographic atrophy secondary to AMD. Geographic atrophy lesion progression over time shows considerable interindividual variability, but little is known about prognostic factors. Objective: To elucidate the contribution of common genetic variants to geographic atrophy lesion growth. Design, Setting, and Participants: This pooled analysis combined 4 independent studies: the Fundus Autofluorescence Imaging in Age-Related Macular Degeneration (FAM) study, the Directional Spread in Geographic Atrophy (DSGA) study, the Age-Related Eye Disease Study (AREDS), and the Geographic Atrophy Treatment Evaluation (GATE) study. Each provided data for geographic atrophy lesion growth in specific designs. Patients with geographic atrophy secondary to AMD were recruited to these studies. Genotypes were retrieved through the database of Genotypes and Phenotypes (for AREDS) or generated at the Cologne Center for Genomics (for FAM, DSGA, and GATE). Main Outcomes: The correlation between square root-transformed geographic atrophy growth rate and 7596219 genetic variants passing quality control was estimated using linear regression. The calculations were adjusted for known factors influencing geographic atrophy growth, such as the presence of bilateral geographic atrophy as well as the number of lesion spots and follow-up times. Main Outcomes and Measures: Slopes per allele, 95% CIs, and P values of genetic variants correlated with geographic atrophy lesion growth. Results: A total of 935 patients (mean [SD] age, 74.7 [7.8] years; 547 female participants [59.0%]) were included. Two gene loci with conservative genome-wide significance were identified. Each minor allele of the genome-wide associated variants increased the geographic atrophy growth rate by a mean of about 15% or 0.05 mm per year. Gene prioritization within each locus suggests the protein arginine methyltransferase 6 gene (PRMT6; chromosome 1; slope, 0.046 [95% CI, 0.026-0.066]; P = 4.09 × 10-8) and the lanosterol synthase gene (LSS; chromosome 21; slope, 0.105 [95% CI, 0.068-0.143]; P = 4.07 × 10-7) as the most likely progression-associated genes. Conclusions and Relevance: These data provide further insight into the genetic architecture of geographic atrophy lesion growth. Geographic atrophy is a clinical outcome with a high medical need for effective therapy. The genes PRMT6 and LSS are promising candidates for future studies aimed at understanding functional aspects of geographic atrophy progression and also for designing novel and targeted treatment options.

Original languageEnglish (US)
JournalJAMA ophthalmology
DOIs
StatePublished - Jan 1 2019

Fingerprint

Geographic Atrophy
Macular Degeneration
Genome
Growth
Genes
Eye Diseases
Protein-Arginine N-Methyltransferases
Alleles
Genotype
Therapeutics

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Assessment of Novel Genome-Wide Significant Gene Loci and Lesion Growth in Geographic Atrophy Secondary to Age-Related Macular Degeneration. / Grassmann, Felix; Harsch, Sebastian; Brandl, Caroline; Kiel, Christina; Nürnberg, Peter; Toliat, Mohammad R.; Fleckenstein, Monika; Pfau, Maximilian; Schmitz-Valckenberg, Steffen; Holz, Frank G.; Chew, Emily Y.; Swaroop, Anand; Ratnapriya, Rinki; Klein, Michael; Mulyukov, Zufar; Zamiri, Parisa; Weber, Bernhard H.F.

In: JAMA ophthalmology, 01.01.2019.

Research output: Contribution to journalArticle

Grassmann, F, Harsch, S, Brandl, C, Kiel, C, Nürnberg, P, Toliat, MR, Fleckenstein, M, Pfau, M, Schmitz-Valckenberg, S, Holz, FG, Chew, EY, Swaroop, A, Ratnapriya, R, Klein, M, Mulyukov, Z, Zamiri, P & Weber, BHF 2019, 'Assessment of Novel Genome-Wide Significant Gene Loci and Lesion Growth in Geographic Atrophy Secondary to Age-Related Macular Degeneration', JAMA ophthalmology. https://doi.org/10.1001/jamaophthalmol.2019.1318
Grassmann, Felix ; Harsch, Sebastian ; Brandl, Caroline ; Kiel, Christina ; Nürnberg, Peter ; Toliat, Mohammad R. ; Fleckenstein, Monika ; Pfau, Maximilian ; Schmitz-Valckenberg, Steffen ; Holz, Frank G. ; Chew, Emily Y. ; Swaroop, Anand ; Ratnapriya, Rinki ; Klein, Michael ; Mulyukov, Zufar ; Zamiri, Parisa ; Weber, Bernhard H.F. / Assessment of Novel Genome-Wide Significant Gene Loci and Lesion Growth in Geographic Atrophy Secondary to Age-Related Macular Degeneration. In: JAMA ophthalmology. 2019.
@article{d559e55022f64c709c8ea5cd3c12320c,
title = "Assessment of Novel Genome-Wide Significant Gene Loci and Lesion Growth in Geographic Atrophy Secondary to Age-Related Macular Degeneration",
abstract = "Importance: Age-related macular degeneration (AMD) is a common threat to vision loss in individuals older than 50 years. While neovascular complications in AMD are treatable, there is currently no therapy for geographic atrophy secondary to AMD. Geographic atrophy lesion progression over time shows considerable interindividual variability, but little is known about prognostic factors. Objective: To elucidate the contribution of common genetic variants to geographic atrophy lesion growth. Design, Setting, and Participants: This pooled analysis combined 4 independent studies: the Fundus Autofluorescence Imaging in Age-Related Macular Degeneration (FAM) study, the Directional Spread in Geographic Atrophy (DSGA) study, the Age-Related Eye Disease Study (AREDS), and the Geographic Atrophy Treatment Evaluation (GATE) study. Each provided data for geographic atrophy lesion growth in specific designs. Patients with geographic atrophy secondary to AMD were recruited to these studies. Genotypes were retrieved through the database of Genotypes and Phenotypes (for AREDS) or generated at the Cologne Center for Genomics (for FAM, DSGA, and GATE). Main Outcomes: The correlation between square root-transformed geographic atrophy growth rate and 7596219 genetic variants passing quality control was estimated using linear regression. The calculations were adjusted for known factors influencing geographic atrophy growth, such as the presence of bilateral geographic atrophy as well as the number of lesion spots and follow-up times. Main Outcomes and Measures: Slopes per allele, 95{\%} CIs, and P values of genetic variants correlated with geographic atrophy lesion growth. Results: A total of 935 patients (mean [SD] age, 74.7 [7.8] years; 547 female participants [59.0{\%}]) were included. Two gene loci with conservative genome-wide significance were identified. Each minor allele of the genome-wide associated variants increased the geographic atrophy growth rate by a mean of about 15{\%} or 0.05 mm per year. Gene prioritization within each locus suggests the protein arginine methyltransferase 6 gene (PRMT6; chromosome 1; slope, 0.046 [95{\%} CI, 0.026-0.066]; P = 4.09 × 10-8) and the lanosterol synthase gene (LSS; chromosome 21; slope, 0.105 [95{\%} CI, 0.068-0.143]; P = 4.07 × 10-7) as the most likely progression-associated genes. Conclusions and Relevance: These data provide further insight into the genetic architecture of geographic atrophy lesion growth. Geographic atrophy is a clinical outcome with a high medical need for effective therapy. The genes PRMT6 and LSS are promising candidates for future studies aimed at understanding functional aspects of geographic atrophy progression and also for designing novel and targeted treatment options.",
author = "Felix Grassmann and Sebastian Harsch and Caroline Brandl and Christina Kiel and Peter N{\"u}rnberg and Toliat, {Mohammad R.} and Monika Fleckenstein and Maximilian Pfau and Steffen Schmitz-Valckenberg and Holz, {Frank G.} and Chew, {Emily Y.} and Anand Swaroop and Rinki Ratnapriya and Michael Klein and Zufar Mulyukov and Parisa Zamiri and Weber, {Bernhard H.F.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1001/jamaophthalmol.2019.1318",
language = "English (US)",
journal = "JAMA Ophthalmology",
issn = "2168-6165",
publisher = "American Medical Association",

}

TY - JOUR

T1 - Assessment of Novel Genome-Wide Significant Gene Loci and Lesion Growth in Geographic Atrophy Secondary to Age-Related Macular Degeneration

AU - Grassmann, Felix

AU - Harsch, Sebastian

AU - Brandl, Caroline

AU - Kiel, Christina

AU - Nürnberg, Peter

AU - Toliat, Mohammad R.

AU - Fleckenstein, Monika

AU - Pfau, Maximilian

AU - Schmitz-Valckenberg, Steffen

AU - Holz, Frank G.

AU - Chew, Emily Y.

AU - Swaroop, Anand

AU - Ratnapriya, Rinki

AU - Klein, Michael

AU - Mulyukov, Zufar

AU - Zamiri, Parisa

AU - Weber, Bernhard H.F.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Importance: Age-related macular degeneration (AMD) is a common threat to vision loss in individuals older than 50 years. While neovascular complications in AMD are treatable, there is currently no therapy for geographic atrophy secondary to AMD. Geographic atrophy lesion progression over time shows considerable interindividual variability, but little is known about prognostic factors. Objective: To elucidate the contribution of common genetic variants to geographic atrophy lesion growth. Design, Setting, and Participants: This pooled analysis combined 4 independent studies: the Fundus Autofluorescence Imaging in Age-Related Macular Degeneration (FAM) study, the Directional Spread in Geographic Atrophy (DSGA) study, the Age-Related Eye Disease Study (AREDS), and the Geographic Atrophy Treatment Evaluation (GATE) study. Each provided data for geographic atrophy lesion growth in specific designs. Patients with geographic atrophy secondary to AMD were recruited to these studies. Genotypes were retrieved through the database of Genotypes and Phenotypes (for AREDS) or generated at the Cologne Center for Genomics (for FAM, DSGA, and GATE). Main Outcomes: The correlation between square root-transformed geographic atrophy growth rate and 7596219 genetic variants passing quality control was estimated using linear regression. The calculations were adjusted for known factors influencing geographic atrophy growth, such as the presence of bilateral geographic atrophy as well as the number of lesion spots and follow-up times. Main Outcomes and Measures: Slopes per allele, 95% CIs, and P values of genetic variants correlated with geographic atrophy lesion growth. Results: A total of 935 patients (mean [SD] age, 74.7 [7.8] years; 547 female participants [59.0%]) were included. Two gene loci with conservative genome-wide significance were identified. Each minor allele of the genome-wide associated variants increased the geographic atrophy growth rate by a mean of about 15% or 0.05 mm per year. Gene prioritization within each locus suggests the protein arginine methyltransferase 6 gene (PRMT6; chromosome 1; slope, 0.046 [95% CI, 0.026-0.066]; P = 4.09 × 10-8) and the lanosterol synthase gene (LSS; chromosome 21; slope, 0.105 [95% CI, 0.068-0.143]; P = 4.07 × 10-7) as the most likely progression-associated genes. Conclusions and Relevance: These data provide further insight into the genetic architecture of geographic atrophy lesion growth. Geographic atrophy is a clinical outcome with a high medical need for effective therapy. The genes PRMT6 and LSS are promising candidates for future studies aimed at understanding functional aspects of geographic atrophy progression and also for designing novel and targeted treatment options.

AB - Importance: Age-related macular degeneration (AMD) is a common threat to vision loss in individuals older than 50 years. While neovascular complications in AMD are treatable, there is currently no therapy for geographic atrophy secondary to AMD. Geographic atrophy lesion progression over time shows considerable interindividual variability, but little is known about prognostic factors. Objective: To elucidate the contribution of common genetic variants to geographic atrophy lesion growth. Design, Setting, and Participants: This pooled analysis combined 4 independent studies: the Fundus Autofluorescence Imaging in Age-Related Macular Degeneration (FAM) study, the Directional Spread in Geographic Atrophy (DSGA) study, the Age-Related Eye Disease Study (AREDS), and the Geographic Atrophy Treatment Evaluation (GATE) study. Each provided data for geographic atrophy lesion growth in specific designs. Patients with geographic atrophy secondary to AMD were recruited to these studies. Genotypes were retrieved through the database of Genotypes and Phenotypes (for AREDS) or generated at the Cologne Center for Genomics (for FAM, DSGA, and GATE). Main Outcomes: The correlation between square root-transformed geographic atrophy growth rate and 7596219 genetic variants passing quality control was estimated using linear regression. The calculations were adjusted for known factors influencing geographic atrophy growth, such as the presence of bilateral geographic atrophy as well as the number of lesion spots and follow-up times. Main Outcomes and Measures: Slopes per allele, 95% CIs, and P values of genetic variants correlated with geographic atrophy lesion growth. Results: A total of 935 patients (mean [SD] age, 74.7 [7.8] years; 547 female participants [59.0%]) were included. Two gene loci with conservative genome-wide significance were identified. Each minor allele of the genome-wide associated variants increased the geographic atrophy growth rate by a mean of about 15% or 0.05 mm per year. Gene prioritization within each locus suggests the protein arginine methyltransferase 6 gene (PRMT6; chromosome 1; slope, 0.046 [95% CI, 0.026-0.066]; P = 4.09 × 10-8) and the lanosterol synthase gene (LSS; chromosome 21; slope, 0.105 [95% CI, 0.068-0.143]; P = 4.07 × 10-7) as the most likely progression-associated genes. Conclusions and Relevance: These data provide further insight into the genetic architecture of geographic atrophy lesion growth. Geographic atrophy is a clinical outcome with a high medical need for effective therapy. The genes PRMT6 and LSS are promising candidates for future studies aimed at understanding functional aspects of geographic atrophy progression and also for designing novel and targeted treatment options.

UR - http://www.scopus.com/inward/record.url?scp=85066756775&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066756775&partnerID=8YFLogxK

U2 - 10.1001/jamaophthalmol.2019.1318

DO - 10.1001/jamaophthalmol.2019.1318

M3 - Article

JO - JAMA Ophthalmology

JF - JAMA Ophthalmology

SN - 2168-6165

ER -